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,1
*
Laboratoire de Biochimie et Pharmacognosie, Département de Biologie, Faculté des Sciences, Université Moulay Ismaïl, Meknès, Maroc, and
Laboratoire de Biologie Cellulaire, WHO Collaborating Center, Université Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium
1To whom correspondence should be addressed at Dr. B. Reusens, Laboratoire de Biologie Cellulaire (BANI/CELL), Université Catholique de Louvain, Place Croix du Sud 5, B 1348 Louvain-la-Neuve, Belgium. E-mail: Reusens{at}bani.ucl.ac.be
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • protein-malnutrition • vascularization • cerebral cortex • brain composition • rats
|
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Nonfatal stroke is also more frequent in adult
women who were small for gestational age (Rich-Edwards et al. 1997
). Diabetes and also hypertension are more likely to
develop at adulthood in people who had a low birth weight (Hales and Barker 1992
). Thus, chronic degenerative diseases such as
vascular disease, diabetes and hypertension might originate in
derangements affecting fetal development (Goldberg and Prentice 1994
). In rats, a low birth weight may be induced in pups when
dams are fed by an isocaloric low protein (LP) diet during pregnancy
(Snoeck et al. 1990
). The offspring may retain lasting
anatomical and functional defects at adulthood in different organs. The
islets of Langerhans of pups born to LP diet-fed dams are affected
in their morphology and function (Snoeck et al. 1990
)
with consequences during adulthood (Dahri et al. 1991
,
Dahri et al. 1995
). Moreover, these alterations at birth
are associated with a deficient vascularization of the islets
(Snoeck et al. 1990
). Likewise, other studies showed
that the number of renal glomeruli is reduced in these pups
(Merlet-Benichou et al. 1994
) and remains low when a
normal diet is given after birth. Anatomical and physiological
variables in the brain of this offspring are also altered when a LP
diet is given to the dams before and during pregnancy. The number of
dendrites is reduced. The sensory cortico-cortical- and
thalamo-cortical-evoked potentials are lower, and the brain tissue has
elevated biogenic amines with modification in tryptophan metabolism
(Resnick et al. 1979
). Vascular bed density of the brain
is influenced by metabolic requirements, at least in normal adult rats
(Bar 1980
). Hence, the LP diet modifies the metabolic
environment of the fetus and leads to alterations of cerebral
variables. The effect of the LP diet on brain vascularization of the
newborn and 30-d-old pups has already been investigated (Conradi et al. 1979
), but its putative lasting consequences at
adulthood were not investigated and require further exploration. The aim of this study was therefore to explore the vascularization and composition of the neonatal brain when an isocaloric LP diet is given to the dams during pregnancy as well as to evaluate the capacity of recovery when a normal diet is given postnatally. To that end, morphological measurements of blood vessel density were performed on neonatal and adult brain sections from animals submitted to LP diet during fetal life only or until adulthood. To further assess the specificity of sensitivity of the brain vascularization to the LP intake, a comparative study was designed on the endocrine pancreas and duodenum vascularization.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Virgin female Wistar rats, 110 d old weighing 200 g
belonging to a local stock bred at the Animal Center of the University
of Louvain, Belgium, were caged with males overnight, and pregnancy was
determined by inspection of vaginal smears. Pregnant rats were kept in
individual cages, at 24°C and 60% humidity, under controlled
dark-light cycle (10 and 14 h). The rats were given free
access to their respective diets and to water. They were divided
randomly into two groups from d 1 of gestation until parturition: one
control (C)2
group was provided with a 20% protein diet, and the second LP group
with an 8% protein diet. Both diets were purchased from Hope Farms
(Woerden, The Netherlands). The diets were similar in fat content and
were rendered isocaloric by the addition of carbohydrates to the LP
diet (Table 1
).The food intake was similar during gestation in both groups of rats as
in our previous study (Snoeck et al. 1990
) and was
slightly lower in the LP adults as also reported previously
(Dahri et al. 1995
).
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At either 3 or 110 d of age, rats were weighed and killed by decapitation. The whole brain was quickly removed and dissected into forebrain and cerebellum. The weights were recorded separately. The tissues were then immediately homogenized in 5 mL of phosphate-buffered saline with Ultra-Turrax for 2–3 min and stored as 3 aliquots at -20°C before analysis.
The institution's guide for the care and use of laboratory animals was followed, and all procedures were performed with approval of the animal ethics committees of the Université Catholique de Louvain, Belgium.
Analytical methods
Proteins in the samples were determined by the method of
Bradford. The DNA assay of Kapuscinski and Skoczylas (1977)
was slightly modified. The 500 µL of homogenized
samples were transferred into tubes and adjusted to 2.5 mL with buffer
to which 500 µL of a DAPI (4', 6-diamidino-2-phenylindole-2-HCl)
solution (125 µg/L; Serva Feinbiochemica, Heidelberg, Germany) were
added. Fluorescence was measured in a Kontron fluorimeter
(Zürich, Switzerland), using calf thymus DNA (Boehringer,
Mannheim, Germany) up to 150 µg/L as standard. The excitation and
emission wave lengths were 370 nm and 460 nm, respectively. Cholesterol
and phospholipids were measured enzymatically (Boehringer), using,
respectively, the methods of Kattermann et al. (1984)
and Takayama et al. (1977)
.
Morphometrical analysis
Cerebral cortex.
The cerebral cortex vascularization from 3-d-old pups or adult female
rats (90-d-old) was studied on thick sections. Animals were killed
under ether anesthesia and perfused intra-aortically with a nuclear
track emulsion (L-4 Ilford) according to the method of de Paermentier et al. (1986)
. Three-day-old rats were perfused
first with 3 mL of a washing solution (8 g/L of NaCl, 1 g/L of procaine
hydrochloride and 1 g/L of glucose) and 5 mL of the diluted (1:4)
emulsion at 37°C, at the rate of 30 mL/h. Adult female rats were
perfused with 30 mL of a washing solution and 50 mL of the diluted
emulsion. The forebrain which included telencephalon, diencephalon and
mesencephalon was dissected, fixed overnight in 40 g/L paraformaldehyde
in 0.1 mol/L of phosphate buffer, at pH 7.4. After dehydration, the
forebrain was cut into three blocks (anterior, median and posterior)
and embedded in polyethylene glycol 1000 (PEG 1000; Acros Organics,
Geel, Belgium). A 30-µm thick section was cut transversally in each
block. The sections were photographically developed for 5 min at room
temperature in D19 developer (Kodak, Chalon-sur-Saone, France). After a
rapid rinse in distilled water, the sections were fixed for 5 min in
sodium thiosulfate (300 g/L) (Janssen Chemica, Beerse, Belgium), then
rinsed again in distilled water, stained with light green (1 g/L in
distilled water), dehydrated, mounted and studied microscopically.
To validate the technique of emulsion perfusion, the vascularization of adult female rats was also studied on thin sections. Anesthetized rats were killed by an intra-aortic perfusion of fixative mixture (paraformaldehyde 40 g/L, lysine 75 mmol/L, and periodate 20 mmol/L. The fixation of the brain was continued for 4 h in the same mixture, followed by dehydration and embedding in PEG 1000. Section of 6 µm was stained with a solution of ammonium oxalate 20 g/L, Arsenazo III 10 g/L (Sigma, Bornem, Belgium).
The length and perimeter of the blood vessels in the cerebral cortex were measured, respectively, on thick and thin sections using an electronic planimeter (MOP Digiplan, Kontron, Germany) and reported to the cortex area measured, giving a blood vessel density. Four fields per section (two fields closed to the plane of symmetry and two other fields lateral) were selected on the three sections. Each field contained 160 mm2. All vessels, including terminal and lateral branches, were measured in each field and values were summed.
Duodenum. Since the analysis of the perfused of emulsion gave inconsistent results in the neonates, measurements were only calculated in adult animals. Three 20-µm sections and four fields per section were analyzed per animal using the method described above for brain.
Endocrine pancreas. Pancreas of the neonates and adult rats were removed. Pieces of pancreas were fixed for 2 h in glutaraldehyde (25 g/L) in 0.1 mol/L of phosphate buffer pH 7.2, rinsed and fixed in osmium tetroxide (10 g/L) in phosphate buffer for 1 h. The samples were washed in phosphate buffer, dehydrated in ethanol and embedded in epon. Three sections (1 µm) were taken at random from each sample of pancreas. After staining with toluidine blue, blood vessel volume density in the islets was calculated as the ratio of intrainsular blood vessel area to islet tissue and reported as percentage.
Statistical analysis
Data were analyzed by one-way ANOVA including the Bartlett test for homogeneity of variance, followed by Scheffé's tests. Differences were considered significant when P < 0.05. Values presented are means ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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LP offspring had lower body weight (-23%, P < 0.01)
at 3 d of age compared to C (Table 2
).The reduction persisted until adulthood when malnutrition was prolonged
postnatally. In R adult rats, body weight was not different from that
of C rats.
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DNA, protein and lipid concentration
In 3-d-old LP pups, DNA concentration was 43% lower in the
forebrain (P < 0.05) and 50% higher in the
cerebellum, compared to C pups (Table 3
).Protein concentration was not different from C in either part of the
brain. In adult LP rats, DNA, protein and cholesterol concentrations
were significantly lower in the forebrain and the cerebellum, but
phospholipids were lower only in the cerebellum. The normal diet given
after birth in the R group restored to normal the DNA, protein,
cholesterol and phospholipid concentrations in both parts of the brain.
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The vascularization of the cerebral cortex in 3-d-old pups born from
dams fed a LP diet was analyzed by measuring the length of blood vessel
profiles on thick sections. The density reached 54.8 ± 5.4
mm/mm2 in C pups but 72% lower, 15.2 ± 2.6
mm/mm2, in LP pups (n = 7/group,
P < 0.01). In adult rats, the density of the blood
vessel profiles estimated by either length or perimeter (see the
Materials and Methods section) was respectively reduced relative to C
by about 35% (P < 0.05) and 43% (P
< 0.001) in the LP group and by 30% (<0.05) and 33%
(P < 0.05) in the R group (Figs. 1
and 2)
.
|
|
).Blood vessel density was significantly lower in the islets of LP adult
rats (P < 0.01) than C and R rat islets, which did not
differ from one another.
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.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In another experiment in which pups were underfed
after birth, fewer capillary profiles were also found per unit area
section in the cortex of 30-d-old pups; however, the fraction of
section area occupied by capillary lumen was normal due to a
compensatory increase in mean cross-sectional area (Peeling and Smart 1994b
). In our experiments, we found also a decrease
in length density of the vessels on section area which would reflect a
reduced number of vessel profiles. Possibly the thinnest capillaries
may be weakly perfused by the emulsion marker, thereby hampering their
identification. However, in comparing the C with experimental group, a
change in vascularization due to the LP diet is observed. In addition,
the vascular quantifications in rats, by use of two different
techniques, revealed the same difference between the groups, validating
once more the methodology used. To our knowledge, it is the first time
that the recovery of brain blood vessel alterations by a normal diet
given immediately after birth to LP newborns has been investigated. It
is worth noting that other anatomical and physiological changes in
developing brain are graded according to the quantity of
protein intake (Resnick et al. 1982
) and are not
restored with a normal protein diet postnatally (Resnick et al. 1979
, Stern et al. 1984
). These perturbations
are associated with behavioral changes. It is unclear if the
alterations in the vascular system are the cause or the consequence of
the quantitative biochemical modifications in the brain tissue, or if
the observed changes in the blood vessels and the neural tissue are
independent. The latter may be more likely since in our study, the
forebrain weight and composition recovered with a normal diet after
birth but the blood vessels did not. In the 3-d-old LP pups and the
adult R rats, we observed a reduced vascular density in the presence of
a normal weight of the forebrain. A normal growth of neural tissue may
then occur despite such an alteration in vascularization, indicating
that the density of the vascular bed might not be a critical limitation
in terms of growth. Blood perfusion to the brain may be normal,
notwithstanding lessened vascular density, and could account for the
maintenance of normal brain weight. We have not measured the blood flow
in the brain. Although, in the endocrine pancreas of our LP adult rats,
where the blood vessel density was lower, we previously showed that
blood flow was lower in basal state, but reached the level observed in
C rats when stimulated with glucose. In the duodenum, where the blood
vessel density was also lower, the basal blood flow was normal
(Iglésias-Barreira et al. 1996
). These
observations show that a reduced vascular density does not always lead
to lower tissue perfusion.
The total brain weight was lower in the LP pups and LP adults, but,
relative to body weight, was significantly higher. Therefore, the brain
is less affected than the body, consistent with a study in LP neonates
(Resnick et al. 1982
) and in underfed pups at 30 d
(Peeling and Smart 1994a
). This may be due to the
direction of nutrients to the brain at the detriment of other
organs. The newborns which have a low body weight as in our study
(Snoeck et al. 1990
) have a normal absolute forebrain
weight. Although DNA concentration was lower in the forebrain, protein
concentration was in the normal range in 3-d-old LP pups, in agreement
with Prasard (1991)
. Both parameters as well as
cholesterol and phospholipid levels remained low in the adult brain
when the LP diet was maintained postnatally but normalized when a
normal diet was given immediately after birth. Similar observations of
recovery after LP diet during fetal life only have been described in
rats at 13 d (Shambaugh et al. 1995
). Cerebellum
weight, in contrast to the forebrain weight, was lower in 3-d-old LP
pups. The greater magnitude of change in the cerebellum is a reflection
of its different growth rate rather than a selective sensitivity of
this organ to malnutrition (Peeling and Smart 1991
,
Shambaugh et al. 1995
). The normalization of the weight
of the cerebellum at adulthood by a normal diet given immediately after
birth confirms earlier results (Winick et al. 1968
).
However, if the LP diet is more severe during fetal life (6%), the
brain weight remains lower at 21 d of age despite a normal diet
after birth (Resnick et al. 1982
) which confirms the
graded effect of the LP content in the diet during gestation.
The development of blood vessels during the fetal growth phase may be
affected by the hormonal changes induced by the LP diet. Insulin is
reduced in the pancreas of fetuses from rat dams fed the LP diet
(Snoeck et al. 1990
) and is thought to be a growth
factor for endothelial cells in particular microvessels (Crow et al. 1994
). Plasma insulin-like growth factor (IGF) levels
are lower in the LP fetus (Muaku et al. 1995
,
Shambaugh et al. 1995
) and IGF stimulate proliferation
of endothelial cells and blood vessel formation (Davies and Hagen 1993
). A LP diet was also shown to reduce the activity of
the placental enzyme 11ß-hydroxysteroid dehydrogenase
(Langley-Evans 1994
), leading to an increased placental
passage of glucocorticoids to the fetus. Glucocorticoids are potent
inhibitors of angiogenesis (Crum et al. 1985
). Decreases
in nutrient availability, such as of amino acids, may also play a role
in the reduction of vascularization. Indeed high doses of
L-amino acids added or not to glutamine favor long-term
growth of endothelial cells (Gorman et al. 1996
).
Moreover, protein deficiency was demonstrated to have an etiological
role in the induction of both vascular and cardiac changes in subadult
monkeys (Sandhyamani 1992
). Notably essential amino
acids as well as taurine and alpha aminobutyric acid plasma levels are
lowered in our LP fetuses (Reusens et al. 1995
). The
precise role of amino acids on endothelial cell growth is not
well-known, but increased homocysteine plasma levels in men prior
to their cardiovascular disease suggested their implication in the
disease (Nygard et al. 1997
).
The most important finding of this study is the dramatic reduction of
brain vascularization, which does not recover with a normal diet
postnatally. In contrast, the vascularization of the endocrine
pancreas, which was also affected at birth was restored at adulthood
when a normal protein diet was given from birth onward. Although the
vascularization of the neonatal duodenum is altered when the dams have
metabolic alterations such as diabetes (Reusens-Billen et al. 1989
), the duodenum showed normal vascularization when a normal
diet was given until adulthood after exposure to a LP diet. The former
observations indicate the possible recovery of the vascular changes,
especially in organs with a higher developmental plasticity, like the
endocrine pancreas and the digestive tract. In those organs,
vascularization was, however, most impaired at adulthood when the rats
were fed a LP diet throughout life. Moreover, this impairment of the
vascularization was demonstrated to have functional consequences in
these organs. Basal blood flow was shown to be significantly decreased
in islets as well as in exocrine pancreas but was normal in duodenum,
colon and kidney in adult rats chronically exposed to 8% protein since
early fetal development. Those functional defects were corrected at
adulthood when LP pups were given a normal protein diet postnatally
(Iglesias-Barreira et al. 1996
). Notably that blood
pressure was normal in the three experimental groups
(unpublished data, Iglesias-Barreira and
Reusens).
To conclude, protein deficiency during gestation reduces the development of the cerebral cortex vascularization which does not recover with a normal diet after birth. The biochemical factors involved in this alteration must be specified as well as the increased vulnerability at adulthood to aggressive situations like hypoxia-, hyper- or hypoglycemia. The permanent effect of fetal protein malnutrition on blood vessels' development irrespective of postnatal nutrition seems to be specific for the brain. Therefore the vascular bed of each organ appears to have its own sensitivity to a LP diet during development. Further experimental investigations on blood vessel development are required to understand the specific consequences of chronic protein undernutrition on pathological vascular diseases later in life, especially in socio-economically unprivileged populations.
Epidemiological observations in humans who have had poor fetal growth
as indicated by a low birth weight and poor infant growth have a higher
incidence of stroke, cardiovascular disease and type 2 diabetes later
in life (Barker et al. 1993
, Hales and Barker 1992
, Rich-Edwards et al. 1997
). Our present
experimental data on cerebral vessels support such former findings.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received May 12, 1998. Initial review completed July 30, 1998. Revision accepted May 18, 1999.
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 S. Boujendar, E. Arany, D. Hill, C. Remacle, and B. Reusens Taurine Supplementation of a Low Protein Diet Fed to Rat Dams Normalizes the Vascularization of the Fetal Endocrine Pancreas J. Nutr., September 1, 2003; 133(9): 2820 - 2825. [Abstract] [Full Text] [PDF]
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 J. Liu, A. Raine, P. H. Venables, C. Dalais, and S. A. Mednick Malnutrition at Age 3 Years and Lower Cognitive Ability at Age 11 Years: Independence From Psychosocial Adversity Arch Pediatr Adolesc Med, June 1, 2003; 157(6): 593 - 600. [Abstract] [Full Text] [PDF]
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 M. Srinivasan, S. G. Laychock, D. J. Hill, and M. S. Patel Neonatal Nutrition: Metabolic Programming of Pancreatic Islets and Obesity Experimental Biology and Medicine, January 1, 2003; 228(1): 15 - 23. [Abstract] [Full Text] [PDF]
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 P. D. Gluckman Editorial: Nutrition, Glucocorticoids, Birth Size, and Adult Disease Endocrinology, May 1, 2001; 142(5): 1689 - 1691. [Full Text]
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H. Cherif, B. Reusens, S. Dahri, and C. Remacle A Protein-Restricted Diet during Pregnancy Alters in Vitro Insulin Secretion from Islets of Fetal Wistar Rats J. Nutr., May 1, 2001; 131(5): 1555 - 1559. [Abstract] [Full Text]
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 M. S. Patel and M. Srinivasan Metabolic Programming: Causes and Consequences J. Biol. Chem., January 11, 2002; 277(3): 1629 - 1632. [Full Text] [PDF]
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